Establishment and evaluation of mouse models of hepatic sinusoidal obstruction syndrome induced by three pyrrolidine alkaloids / 中华消化杂志

ABSTRACT

Objective:To establish and evaluate acute hepatic sinusoidal obstruction syndrome (HSOS) mouse models induced by three pyrrolidine alkaloids (PAs) including monocrotaline (MCT), retrorsine (RTS) and senecionine (SEN).Methods:Forty-eight male C57 mice were divided into four groups, control group, MCT group, RTS group and SEN group, with 12 mice in each group, which were gavaged once with phosphate buffer saline (300 μL), MCT solution (800 mg/kg), RTS solution (100 mg/kg) and SEN solution (100 mg/kg), respectively. At 24 hours after gavage, the number of mortality and success modeling, liver function, and pathological changes of liver of four groups of mice were analyzed. One way analysis of variance, Bonferroni test and Chi-square test were used for statistical analysis.Results:At 24 hours after gavage, the number of dead mice of MCT group, RTS group and SEN group was zero, nine and zero, respectively; and the number of survival successfully modeled mice was nine, three and six, respectively; the difference of mortality among three groups was statistically significant ( χ2=21.734, P<0.05), and the difference of the number of success modeling was not statistically significant ( χ2=2.836, P>0.05). The alanine aminotransferase (ALT) levels of MCT group, RTS group and SEN group were (111.72±37.62), (562.97±242.42) and (3 891.40±1 009.44) U/L, respectively; aspartate transaminase (AST) levels were (156.96±64.95), (331.22±120.83) and (2 107.55±532.80) U/L, respectively; and total bilirubin (TBil) levels were (41.66±10.42), (79.43±18.45) and (120.80±17.44) μmol/L, respectively, which were all higher than those of the control group ((31.40±10.98) U/L, (34.66±13.00) U/L and (16.91±2.89) μmol/L, respectively); and the differences were statistically significant (Bonferroni test, all P<0.008 3). There were statistically significant differences in ALT and AST levels between MCT group and RTS group (Bonferroni test, both P<0.008 3), while there was no statistically significant difference in TBil level between two groups ( P>0.008 3). There was statistically significant difference in TBil level between MCT group and SEN group (Bonferroni test, P=0.002), however there were no statistically significant differences in ALT and AST levels between two groups (both P>0.008 3). There were statistically significant differences in ALT, AST and TBil levels between RTS group and SEN group (Bonferroni test, all P<0.008 3). The mouse liver tissues of all three groups showed coagulative necrosis of hepatocytes, subendothelial hemorrhage of central vein, the dilation of hepatic sinusoids, erythrocyte clogging in the space of disse, and destruction of normal lobular structure. In MCT and RTS groups, the main damages were hepatocyte necrosis, sinusoidal dilatation and congestion in zone 3 of the liver acinus, while in SEN group, which were hepatocyte necrosis and sinusoidal congestion in zone 1 and 2 of the liver acinus. The histological changes of mouse liver tissues of MCT group were moderate to severe, and those of RTS group and SEN group were all severe. Conclusions:Acute HSOS mouse models induced by three kinds of PA including MCT, RTS and SEN are successfully established, of which MCT is the most suifable choice.